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Glutathione Transferase Deficient Mice To Probe For Adverse Drug Reactions
Funder
National Health and Medical Research Council
Funding Amount
$562,933.00
Summary
A family of enzymes called glutathione transferases (GST) that metabolize foreign chemicals and therapeutic drugs have been shown to be a significant cause of drug resistance in cancer chemotherapy. It has been suggested that inhibitors of GSTs could be used in cancer treatment to counter drug resistance or to slow the metabolism and enhance the activity of some drugs. Some GSTs carryout important enzymatic reactions with endogenous substrates and others have important non-enzymatic functions su ....A family of enzymes called glutathione transferases (GST) that metabolize foreign chemicals and therapeutic drugs have been shown to be a significant cause of drug resistance in cancer chemotherapy. It has been suggested that inhibitors of GSTs could be used in cancer treatment to counter drug resistance or to slow the metabolism and enhance the activity of some drugs. Some GSTs carryout important enzymatic reactions with endogenous substrates and others have important non-enzymatic functions such as the regulation of signaling pathways within cells and the modulation of calcium ion channels that are involved in muscle contractions. The generic inhibition of all GSTs could therefore have significant adverse physiological effects. We propose to make mice deficient in specific GSTs and to study their physiological responses. The results of these studies will indicate which GSTs can be safely inhibited without the risk of deleterious side effects. These studies are important because adverse reactions to therapeutic drugs are a significant cause of hospital admissions and death.Read moreRead less
A Biomimetic Prodrug Platform To Enable Oral Bioavailability And Target Lymphatic Disease
Funder
National Health and Medical Research Council
Funding Amount
$408,768.00
Summary
This project will allow the advance of a unique translational technology platform that provides novel drug delivery solutions. The project aims to establish the potential for a drug delivery strategy to increase the efficacy, reduce the toxicity, and transform the impact of drug therapies for a variety of conditions, including pain, hormone dysregulation, and metabolic syndrome.
Drugs are broken down in the body by the process of metabolism. Metabolism is important as both a detoxification and elimination mechanism, and determines dose rate for chronically administered drugs. Many drugs are metabolised by a reaction called glucuronidation. We will characterise the various components of the glucuronidation reaction in an integrated manner in order to understand and predict factors that influence an individual's capacity to metabolise drugs and other chemicals.
Structure, Function And Regulation Of Human Cytosolic Sulfotransferases
Funder
National Health and Medical Research Council
Funding Amount
$265,500.00
Summary
The sulfotransferase family of enzymes serve an important role in the metabolism of drugs and foreign chemicals. They also metabolise a range of chemicals that are normally present in the body such as hormones and substances that are involved in brain function (neurotransmitters). Observations from clinical studies suggest that differences in sulfotransferases activities may be a causal factor in the incidence of certain types of cancer and neurodegenerative diseases. Recent advances in understa ....The sulfotransferase family of enzymes serve an important role in the metabolism of drugs and foreign chemicals. They also metabolise a range of chemicals that are normally present in the body such as hormones and substances that are involved in brain function (neurotransmitters). Observations from clinical studies suggest that differences in sulfotransferases activities may be a causal factor in the incidence of certain types of cancer and neurodegenerative diseases. Recent advances in understanding the molecular biology of these enzymes have shown us that multiple forms of sulfotransferase existed within the body. In this area my laboratory has been at the forefront of the cloning and characterisation of these enzymes. Indeed, we were the first laboratory to clone the major human sulfotransferase (SULT1A3) responsible for the metabolism of brain neurotransmitters. We have also used new technology to determine the shape of this important enzyme. At the time of writing my laboratory has characterised a total seven human sulfotransferases but unlike SULT1A3, our knowledge of the functional significance of the other six sulfotransferase is poorly understood. Further, our knowledge of what regulates the amount of sulfotransferase in different tissues is practically nonexistent. The thrust of this project is to extend our studies on the physiological function of these enzymes and also through the use of molecular biology techniques understand what controls the level of their expression in different human tissues. This knowledge will provide a basis for understanding the role of sulfotransferases play in drug and chemical metabolism. It will also aid our understanding of their role in hormone and neurotransmitter metabolism and help determine whether they are involved in such diseases as cancer and neurodegenerative diseases.Read moreRead less
Regulation Of Human Arylamine N-acetyltransferase Transcription, Translation And Protein Stability
Funder
National Health and Medical Research Council
Funding Amount
$470,958.00
Summary
Individuals respond very differently to many drugs and other chemicals in the diet and workplace. This variation can be a significant complication in treating patients and in attempting to determine risk with exposure to toxins. Genetic differences between individuals are a common reason for this variation. However, many enzymes and other proteins in humans are controlled by environmental factors that can either increase their activity or inhibit it. In this study, we will investigate how the ac ....Individuals respond very differently to many drugs and other chemicals in the diet and workplace. This variation can be a significant complication in treating patients and in attempting to determine risk with exposure to toxins. Genetic differences between individuals are a common reason for this variation. However, many enzymes and other proteins in humans are controlled by environmental factors that can either increase their activity or inhibit it. In this study, we will investigate how the activity of an important family of enzymes (the acetyltransferases) varies between individuals as a result of environmental factors. We will look at the genes for each of the enzymes and learn about this control mechanism. We will also look careful at the structure of the proteins and determine how this may change when challenged with external stimuli. The expected outcome will be a better understanding of these important enzymes that are involved in the metabolism of many drugs, and also provide a means of determining how different individuals may respond to foreign chemicals and drugs that use these enzymes in the body for metabolism.Read moreRead less
Regulation Of Drug Detoxifying UDP Glucuronosyltransferases
Funder
National Health and Medical Research Council
Funding Amount
$590,945.00
Summary
Some organs in the body are particularly sensitive to fat-soluble chemicals taken in from the environment or present in food. They are also sensitive to hormones and other small molecule products of metabolism. Controlling the levels of these potentially toxic chemicals is essential in order to maintain the health of the organ. In this work we will investigate the regulation of detoxifying enzymes that protect these organs by inactivating and hastening the elimination of fat-soluble chemicals.
Role Of The Drug Metabolising Enzyme Arylamine N-acetyltransferase 1 In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$600,196.00
Summary
The current project will identify the molecular mechanism(s) that underpins the significant changes in phenotype seen in a range of human cancer cells. The expected outcomes will be to demonstrate that NAT1 is critical for the clearance of pABG in cancer cells. The results will be important in the context of understanding this family of intracellular enzymes and will change the current thinking on the function of the arylamine N-acetyltransferase in normal and cancer cells.